Difficult Cases: Insect Allergy Jenny Stitt, MD Rohit Katial, MD, FAAAAI

Case 33 yo man stung by an insect on his lower leg while biking. Area began swelling, he took diphenhydramine from his first aid kit By the time he reached his car, 20 minutes later: Hives appeared on his leg, which spread rapidly He had facial swelling and mild wheezing He traveled to the ED where he was treated with IM epinephrine and IV steroids: Symptoms improved after several hours of monitoring He was discharged home with a prednisone burst

Case He felt well until early morning the next day, when diffuse urticaria developed, associated with abdominal pain and nausea Returned to ED, got epinephrine, antihistamines, and IV steroids Symptoms improved, but he was admitted for observation

Case Past Medical History Seasonal Allergic Rhinitis Immunotherapy as a teenager for 5 years, with symptom improvement Exercise-induced Bronchospasm Rarely uses albuterol, bikes up to 50 miles twice weekly Family History: brother with severe asthma, daughter with eczema Social History: office work, no travel, no tobacco or alcohol use Environmental History: lives in a single family home, No pets Medications Azelastine 1 spray each nostril BID Albuterol PRN (no recent uses) Ibuprofen PRN (no recent uses)

Physical Exam T 37.4 P 78 BP 112/72 RR 19 94% RA General: WDWN, NAD HEENT: no angioedema, airway patent Respiratory: no distress, lungs clear Skin: diffuse urticaria

Labs CBC CMP, Coags, UA normal, Utox negative Wbc 17.1 (P 88.3%, L 5.2%, M 6.1%, E 0%) Hgb 15.0, Plt 167 CMP, Coags, UA normal, Utox negative

Case Stable for the remainder of admission. Discharged with autoinjectable epinephrine, on prednisone taper, cetirizine, montelukast. Advised to follow up with allergy as an outpatient for biphasic anaphylaxis after an unknown insect sting.

Question How long after the insect sting should he be advised to schedule follow-up for allergy testing? 1 week 4-6 weeks 12 weeks A and then B if needed A, B or C ANSWER on next slide

Question How long after the insect sting should he be advised to schedule follow-up for allergy testing? 1 week 4-6 weeks 12 weeks A and then B if needed A, B or C

Timing of Venom Testing Historically there was concern for anergic period for several weeks after sting reactions; however this was based on whole body extract testing More recent results suggest the majority of those with systemic reactions demonstrate sensitization after one week

At 4-6 weeks, the remaining 21% had at least one positive result At one week, skin testing and specific IgE identified 79% of those sensitized to venoms At 4-6 weeks, the remaining 21% had at least one positive result Notably 3 patients from original N=41 were excluded, for a total of 38 analyzed one pt excluded from analysis who was negative at initial visit then lost to f/u Two pts excluded who were negative at both time points, one with grade 3 SR No significant difference in sensitivity between skin testing and IgE at week 1 Goldberg. J Allergy Clin Immunology. 1997.

Case About 6 weeks after initial episode he followed up in allergy clinic for skin testing to venoms: Testing was negative to all venoms up to a concentration of 1.0 mcg/mL.

Question When skin testing to venoms is negative after a systemic reaction to an unknown insect sting, what is the next appropriate step? Advise the patient he is not allergic to venoms Start VIT to honeybee, mixed vespid and wasp Check Venom-specific IgE and/or repeat skin tests Repeat skin testing in another 3 months ANSWER on next slide

Question When skin testing to venoms is negative after a systemic reaction to an unknown insect sting, what is the next appropriate step? Advise the patient he is not allergic to venoms Start VIT to honeybee, mixed vespid and wasp Check Venom-specific IgE and/or repeat skin tests Repeat skin testing in another 3 months

Golden et al. J Allergy Clin Immunol. 2011 Apr;127(4):852-4.e1-23. For patients who have had a severe systemic reaction…and who have negative venom skin test responses, it would be prudent to verify this result with repeat skin and in vitro testing before concluding that VIT is not necessary. Golden et al. J Allergy Clin Immunol. 2011 Apr;127(4):852-4.e1-23.

307 patients with histories of systemic reactions to insect stings 99 (32%) with negative skin testing 208 (68%) with positive skin testing 43 (43%) had positive RAST test 56 (57%) had negative RAST test Sting Challenge Of 141 stung, 30 (21%) had Systemic reactions Of 37 stung, 9 (24%) had Systemic Reactions Of 14 stung, 2 (14%) had Systemic reactions Golden. J Allergy Clin Immunology 2001;107:897-901

Case Lab Value Normal Range Total IgE 320 IU/mL 0-180 IU/mL Hymenoptera IgE Honey Bee <0.10 kU/L Paper Wasp White-faced Hornet Yellow-faced Hornet Yellow Jacket

Question After negative skin testing and no detectable venom- specific IgE, what is your next step? Advise the patient he is not allergic to venoms Start VIT to honeybee, mixed vespid and wasp Check tryptase Repeat IgE and skin testing in another 3 months ANSWER on next slide

Question After negative skin testing and no detectable venom- specific IgE, what is your next step? Advise the patient he is not allergic to venoms Start VIT to honeybee, mixed vespid and wasp Check tryptase Repeat IgE and skin testing in another 3 months

“If repeat test responses fail to demonstrate the presence of IgE antibodies, there is no indication for VIT, but baseline serum tryptase levels can be measured to determine whether there is an underlying mast cell disorder” Golden et al. J Allergy Clin Immunol. 2011 Apr;127(4):852-4.e1-23

Question Elevated baseline tryptase is associated with: Severe reactions to insect stings Severe reactions to venom immunotherapy Clonal mast cell disorders on bone marrow biopsy All of the above ANSWER on next slide

Question Elevated baseline tryptase is associated with: Severe reactions to insect stings Severe reactions to venom immunotherapy Clonal mast cell disorders on bone marrow biopsy All of the above

Higher baseline tryptase is associated with higher grade of allergic reactions in venom- allergic patients Haeberli. Clin Exp Allergy 2003; 33:1216-1220

Franziska R. J Allergy Clin Immunol 2010;126:105-11 Observational multicenter study, 680 subjects with honeybee or vespid allergy who underwent VIT 57 (8.4%) required emergency intervention during buildup Frequency of interventions increased with higher baseline tryptase The predictive power of baseline tryptase was markedly greater when VIT was performed for vespid than for bee venom Conclusion: Before vespid VIT, baseline tryptase should be used to identify patients with high risk for side effects Patients with bee venom allergy require a particularly high degree of surveillance during VIT tryptase concentration, age, sex, culprit insect, cardiovascular medication, degree of preceding sting reaction, preventive antiallergic medication before therapy, time between last preceding sting reaction and VIT, venom specific IgE concentration, and type of buildup procedure. Relative rates were calculated with generalized additive models Franziska R. J Allergy Clin Immunol 2010;126:105-11

274 subjects diagnosed with honeybee or wasp venom allergy. Sting reaction severity increased with increased age and tryptase levels. Conclusions: Serum tryptase is a risk factor for severe anaphylactic reactions to hymenoptera stings. Serum tryptase levels increase continuously with age and are an indicator for increased mast cell load, which is partly responsible for the observed aggravated allergic reactions in elderly people These patients are at increased risk for life-threatening anaphylactic reactions and should consider adjustment of VIT in elderly patients with elevated tryptase as recommended for patients with mastocytosis Guenova. Allergy 2010; 65: 919–923.

Elevated tryptase is associated with more severe reactions to hymenoptera stings and may be associated with clonal mast cell disorders Baseline tryptase elevated in 11.6% of those with systemic reactions to hymenoptera stings Associated with higher grades of reaction Bone marrow biopsy performed in 34 of 44 with elevated baseline tryptase Biopsy led to diagnosis of Indolent Systemic Mastocytosis in 21 Monoclonal Mast Cell Activation Syndrome in 9 All 4 with negative venom allergy testing had: Elevated baseline tryptase Mast cell disorders on bone marrow bx Indolent Systemic Mastocytosis in 3 Monoclonal Mast Cell Activation Syndrome in 1 - 44/379 (11.6%) had elevated baseline tryptases - 4/379 had negative skin testing to venoms, all 4 had higher baseline tryptases and were diagnosed with mast cell d/o (3=ISM, 1=MMAS) Bonadonna. J Allergy Clin Immunol 2009;123:680-6.

Even those with normal baseline tryptase may have clonal mast cell disorders on bone marrow biopsy Bone marrow biopsies performed on 22 patients with severe hymenoptera allergy and NORMAL baseline tryptase <11.4 ng/mL 16 had clonal mast cell disorders defined on biopsy Urticaria/angioedema with sting less common (p=0.004) Trend towards higher baseline tryptases (8.6 vs 7.1, p=0.03) Numbers of negative allergy testing similar in both groups Mast cell d/o 1 with MMAS 15 with ISM One in each group had negative allergy testing Zanotti. J Allergy Clin Immunol 2015. In Press

Case Tryptase checked at baseline and was totally normal Total 4.5 ng/mL (normal 1-15, average 5) Mature <1 ng/mL (normal <1 ) He declined further evaluation for mast cell disorder with bone marrow biopsy.

Question With negative skin testing and no detectable specific IgE to venoms, what is his estimated risk for another systemic reaction? <1% 5-10% 25-50% 100% ANSWER on next slide

Question With negative skin testing and no detectable specific IgE to venoms, what is his estimated risk for another systemic reaction? <1% 5-10% 25-50% 100%